The foundation of this project encompasses our studies which over the 30 years' duration of this grant have defined 1) unique oligosaccharide structures as signatures found on specific plasma glycoproteins, 2) the mechanisms of recognition of these structures by carbohydrate-specific endocytic receptors, and 3) the functionally important in vivo biological consequences of this recognition. We have progressed from defining at the molecular and cellular level the biologic basis of oligosaccharide recognition by these receptors to delineating at the whole organism level the functional implications of such recognition. Our progress on how carbohydrate-specific endocytic receptor recognition systems clear particular glycoproteins from the circulation now culminates in a unique opportunity to take these studies to a new level of functional perspective: the mechanisms by which these receptors regulate concentrations of specific plasma proteins. We previously defined how the Mannose/GalNAc-4-SO4-receptor (M/G4S-R) mediates the clearance of glycoproteins that bear the N-linked oligosaccharide signature of terminal GalNAc-4-S04. We have shown by biochemical and genetic means that the asialoglycoprotein-receptor (ASGP-R) mediates the clearance of glycoproteins that bear the N-linked oligosaccharide signature of terminal Siaa2,6GalNAc, and now have evidence that plasma proteins bearing the oligosaccharide signature of terminal Siaa2,6Gal represent the major endogenous ligands for the ASGP-R, giving a significant new functional identity to this receptor as a key regulator of the concentration of numerous plasma glycoproteins that have Siaa2,6Gal termini under physiologic conditions and during the response to sepsis. We will use genetic models and recently established proteomic methods to define the relative roles of the ASGP-R and M/G4S-R, individually and in combination, in regulating the levels of specific plasma glycoproteins under physiologic and pathologic conditions including the acute phase response to sepsis and pregnancy. These proposed studies will not only address how production is balanced with clearance to regulate the plasma levels of many glycoproteins through recognition of their carbohydrate signatures, but will also allow us to determine if perturbing this balance has an impact on biologic processes ranging from the acute phase response to the regulation of estrogen production by glycoprotein hormones. An understanding of these fundamental processes will ultimately yield insights that can aid in evaluating changes in plasma proteins for diagnostic and theraputic purposes.